The most important consequences of lung disease is hypoxemia resulting in paired oxygen supply to the tissues. This research program continues its commitment to understanding the causes and effects of hypoxemia in health and disease. Two of the six projects address this at the level of the lung; the other four focus on the skeletal muscles. All follow the theme of understanding how the structural elements of the O2 transport chain determine and regulate O2 transport. Al projects are led by faculty in the Physiology Division of the Department Of Medicine, with four of the projects continuing from the prior cycle. The program, requesting support for years 26-30, has evolved considerably over the last five years to heavily depend on cellular and molecular techniques applied in physiological circumstances to answer questions of biological and clinical importance. A molecular laboratory and cell culture facility are in place to support this direction. Dr. Wagner addresses the determinants of maximal exercise in health and disease, with a focus on molecular regulation of angiogenesis in muscle. Dr. Mathieu-Costello uses a comparative morphological approach to study muscle capacity for blood-tissue O2 transfer during the aging process. Dr. Richardson deals with effects of age on muscle function, and will develop new magnetic resonance-based methods to study this. Dr. Powell continues to address hypoxic ventilatory responses, using systemic physiological and molecular methods in an integrated program. Dr. Hogan will focus on how O2 regulates muscle function in single fibers. Dr. Breen studies effects of physical stress on lung matrix protein regulation, and also addresses the significance of stress-induced calcyclin gene expression to lung fibroblast cell division. The program is supported by three cores: Morphology/Morphometry and Administrative (continuing from the prior cycle) and a new Molecular Biology core. Our collective goal is to understand how O2 transport between the environment and the mitochondria is regulated in health and disease by applying systemic, cellular and molecular methods to key question in an integrated manner and in physiologically intact systems.